From: Kristel Crommentuyn, pharmD Apkcr@SLZ.NL
Subject: [NMusers] problem with acquiring post hoc estimates  
Date: Tue, May 18, 2004 11:21 am  

Dear all, 

We are experiencing problems with a pk model, in acquiring post hoc estimates and
hope someone will be able to help us

The model describes the pharmacokinetics of an orally dosed compound and its
metabolite in children. The data consists of complete pharmacokinetic curves as well
as sparse samples for 38 subjects at different occasions (1-28). Both parent and
metabolite data are best described with a one-compartment model with first-order
elimination. Cl and V are allometrically scaled for body weight. The frequency of
administration is a covariate on Cl1. 
We would like to generate posthoc estimates for the Cmin of the parent compound and
metabolite to use in a pharmacodynamic analysis. When we use the controlstream
(below) and dataset (enclosed test1.csv) the Cmin posthocs for both compounds are
equal, whereas at the other time-points they differ. 

$PK
TVCL1=THETA(1)*THETA(6)**FREQ
CL1=TVCL1*(WT/18)**0.75*EXP(ETA(1))
TVV1=THETA(2)*(WT/18)**1.0
V1=TVV1*EXP(ETA(2))
K12=CL1/V1
D1=THETA(3)*EXP(ETA(3))
TVCL2=THETA(4)*(WT/18)**0.75
CL2=TVCL2*EXP(ETA(4))
TVV2=THETA(5)*(WT/18)**1.0
V2=TVV2*EXP(ETA(5))
K20=CL2/V2
F1=1*EXP(VF)
S1=V1
S2=V2

I hope that someone can help us with this. 
Best regards, 

Kristel

___________________________________
Kristel Crommentuyn, pharmD
AIDS research pharmacist
Department of Pharmacy and Pharmacology
Slotervaart Hospital
Louwesweg 6
1066 EC Amsterdam
The Netherlands
apkcr@slz.nl
020-5124737

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From: Leonid Gibiansky lgibiansky@emmes.com
Subject: RE: [NMusers] problem with acquiring post hoc estimates  
Date: Tue, May 18, 2004 12:01 pm 

Kristel
Few questions:
It would help to see a full control stream, not only the PK block.
What is VF ?
Why CL1 depends on frequency of administration (THETA(6)**FREQ) ?
How  Cmin is defined?
Why oral dose is modeled as zero-order bolus dose (infusion with duration 
D1) rather than via absorption KA?
I am not 100% sure but I would use EVID=1 rather than EVID=4 at the first 
line of your data set.
Thanks
Leonid

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From: Leonid Gibiansky lgibiansky@emmes.com
Subject: RE: [NMusers] problem with acquiring post hoc estimates  
Date: Tue, May 18, 2004 1:41 pm

Kristel
I do not know why, but with your control stream and data, NONMEM was using 
F in compartment 1 for EVID =2 (only!) even when CMT was equal to 2. You 
may use values that correspond to EVID=0 (3d and 4th lines of your data 
file) or modify the code as below and use C1, C2 or IPRED/PRED (that are 
computed explicitly using A1 and A2 rather than F).
Leonid


$ERROR
C1 = A(1)/S1
C2 = A(2)/S2
IPRED=A(1)/S1
IF(CMT.EQ.2)  IPRED=A(2)/S2
IF(CMT.EQ.1)THEN
Y=IPRED+IPRED*THETA(7)*ERR(1)+THETA(8)*ERR(2)
W=SQRT(IPRED*IPRED*THETA(7)**2+THETA(8)**2)
ELSE
Y=IPRED+IPRED*THETA(9)*ERR(3)+THETA(10)*ERR(4)
W=SQRT(IPRED*IPRED*THETA(9)**2+THETA(10)**2)
ENDIF
IRES=DV-IPRED
IWRES=IRES/W

$TABLE .... CMT C1 C2 IPRED ..

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